Prion disease is a type of amyloidosis, like Alzheimer's disease and type 2 diabetes, but with the important distinction of being infectious. In these diseases abnormal folding of a cellular protein leads to its aggregation into fibrillar structures (amyloid) whose accumulation is associated with tissue degeneration. Our research using yeast as a genetic system is aimed at better understanding amyloid formation and replication, and in particular, what roles cellular factors play in its propagation and transmission. The yeast [PSI] prion is a cytoplasmic amyloid of the translation termination factor Sup35p. When [PSI] is present much of the Sup35p is sequestered into amyloid causing reduced translation termination efficiency. Reduced termination leads to a nonsense suppressor phenotype that is used to monitor [PSI]. [PSI] can be eliminated by growing cells in millimolar amounts of guanidine, which we earlier showed was due to inactivation of the protein chaperone Hsp104. We earlier isolated a mutation of the protein chaperone Hsp70 (SSA1-21) that considerably impairs propagation of the yeast [PSI] prion but has no apparent effect on cell growth. Hsp70 assists protein folding through regulated binding and release of partially folded proteins. To better understand the altered function of the mutant Hsp70 we generated new mutations in SSA1 that similarly impaired [PSI] and intra-allelic mutations of SSA1-21 that restored it. Our results indicate that Hsp70 mutations that promote or prolong the high affinity (substrate-trapping) state of Hsp70 cause impaired prion propagation in yeast. In a separate study we found that mutants of a ribosomal Hsp70 (SSB) were hypersensitive to guanidine and displayed altered translation termination independently of [PSI]. The guanidine hypersensitivity was found to be due to increased uptake of the compound, which did not result from an alteration in membrane lipid composition or of the activity of a major class of membrane transporters. Our data have implications for the previously observed hypersensitivity of SSB mutants to several other compounds. The altered translation termination efficiency was found to be due to stabilization of nonsense containing mRNA, suggesting a role for SSB in mRNA stability.